Physiotherapy 107 (2020) 118–132

Review

Effects of joint mobilisation on clinical manifestations of

sympathetic nervous system activity: a systematic
review and meta-analysis
Marcos J. Navarro-Santana a , Guido F. Gómez-Chiguano b ,
Mihai D. Somkereki i , César Fernández-de-las-Peñas c,∗ ,
Joshua A. Cleland d,e,f , Gustavo Plaza-Manzano g,h
a Rehabilitación San Fernando, Madrid, Spain
b Podiatry Clinic, Faculty of Nursing, Physiotherapy and Podiatry, Universidad Complutense de Madrid, Madrid, Spain
c Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos,
Alcorcón, Madrid, Spain
d Department of Physical Therapy, Franklin Pierce University, Manchester, NH, USA
e Rehabilitation Services, Concord Hospital, Concord, NH, USA
f Manual Therapy Fellowship Program, Regis University, Denver, CO, USA
g Department of Radiology, Rehabilitation and Physiotherapy, Universidad Complutense de Madrid, Madrid, Spain
h Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain
i Clínica de Investigación Fisioterapia y Dolor, Fundación General de la Universidad de Alcalá, Alcalá de Henares, Spain

Abstract
Background A potential mechanism of action of manual therapy is the activation of a sympathetic-excitatory response.
Objective To evaluate the effects of joint mobilisation on changes in clinical manifestations of sympathetic nervous system activity.
Data sources MEDLINE, EMBASE, AMED, CINAHL, EBSCO, PubMed, PEDro, Cochrane Collaboration Trials Register, Cochrane
Database of Systematic Reviews and SCOPUS databases.
Study selection Randomised controlled trials that compared a mobilisation technique applied to the spine or the extremities with a control
or placebo.
Data extraction and data synthesis Human studies collecting data on skin conductance or skin temperature were used. Data were extracted
by two reviewers. Risk of bias was assessed using the Cochrane guidelines, and quality of evidence was assessed using the GRADE approach.
Standardised mean differences (SMD) and random effects were calculated.
Results Eighteen studies were included in the review and 17 were included in the meta-analysis. The meta-analysis found a significant
increase in skin conductance [SMD 1.21, 95% confidence interval (CI) 0.88 to 1.53, n = 269] and a decrease in temperature (SMD 0.92, 95%
CI −1.47 to −0.37, n = 128) after mobilisation compared with the control group. An increase in skin conductance (SMD 0.73, 95% CI 0.51
to 0.96, n = 293) and a decrease in temperature (SMD −0.50, 95% CI −0.82 to −0.18, n = 134) were seen after mobilisation compared with
placebo. The risk of bias was generally low, but the heterogenicity of the results downgraded the level of evidence.
Limitations Most trials (14/18) were conducted on asymptomatic healthy subjects.
Conclusion There is moderate evidence suggesting a sympatho-excitatory effect of joint mobilisation.
Systematic Review Registration Number PROSPERO CRD42018089991.
© 2019 Published by Elsevier Ltd on behalf of Chartered Society of Physiotherapy.

Keywords: Mobilisation; Best evidence; Sympathetic nervous system; Skin conductance; Skin temperature

∗ Corresponding author at: Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avenida de Atenas s/n, 28922 Alcorcón, Madrid, Spain.
E-mail addresses: cesarfdlp@yahoo.es, cesar.fernandez@urjc.es (C. Fernández-de-las-Peñas).

https://doi.org/10.1016/j.physio.2019.07.001
0031-9406/© 2019 Published by Elsevier Ltd on behalf of Chartered Society of Physiotherapy.
 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
Introduction
Manual joint mobilisation is commonly used by phys-
ical therapists to manage musculoskeletal pain [1,2], and
is recommended as a useful therapeutic tool in clinical
practice guidelines [3,4]. Joint mobilisation is defined as
a low-velocity/high-amplitude intervention, as opposed to
manipulation or a high-velocity/low-amplitude intervention.
It has been shown that joint mobilisation techniques may have
a pain-modulating effect by exerting hypoalgesic responses
presenting as an increase in pressure pain threshold [5] or a
decrease in pain [6]. However, the therapeutic mechanisms
for inhibition of pain remain to be elucidated.
There are several potential therapeutic mechanisms that
may contribute to the analgesic effects of manual ther-
apies, including reduction of muscle activity, changes in
neural mechanical sensitivity [7], and changes in endoge-
nous substances or biomarkers (e.g. oxytocin, neurotensin or
substance P) [8,9]. Additionally, there is evidence suggest-
ing that manual therapies activate descending inhibitory pain
responses from central nervous system areas, particularly the
periaqueductal grey matter. This may be related to the fact
that pain modulation associated with joint mobilisation may
stimulate non-opioid central pathways [10].
Another potential mechanism explaining the therapeu-
tic effect of joint mobilisation interventions is the impact
on sympathetic nervous system activity [11]. Some authors
proposed that the sympathetic nervous system is activated
through central brain areas (e.g. periaqueductal grey matter),
and therefore its activation can contribute to a central pain
inhibition response during joint mobilisation. A study on an
animal model found that electrical stimulation in the mid-
brain which originated from the periaqueductal grey matter
resulted in an analgesic response accompanied by sympa-
thetic nervous system activation [11,12]. This hypothesis is
also supported by studies demonstrating that hypoalgesia
induced with manual therapies occurs simultaneously with
a sympathetic-excitatory change in humans [7,13]. There-
fore, changes in sympathetic nervous system activity may be
directly related to modulation responses during therapeutic
interventions.
It has been suggested that stimulation of the sympathetic
trunks can occur as a result of manual therapies applied to the
spine [14,15]. Assessing the response of the sympathetic ner-
vous system typically includes measures of skin conductance
or skin temperature as clinical manifestations. In fact, several
studies have shown increased skin conductance [7,13,15–20],
respiratory rate and heart rate [21] and decreased skin tem-
perature after the application of joint mobilisation targeting
the spine [22,23], suggesting a sympathetic-excitatory effect.
A meta-analysis examining the effects of joint mobilisation
targeting the thoracic and cervical regions found a moder-
ate to high effect on changes in skin conductance and skin
temperature [24], indicating a potential response from the
sympathetic nervous system with these interventions. These
119
findings are supported by another recent systematic review
that examined the mechanisms of spinal mobilisation [25].
However, previous reviews examined the changes associated
with joint techniques directed at the spine, particularly the
cervical and thoracic regions. To the authors’ knowledge,
no meta-analysis to date has examined the effects of joint
mobilisation targeting the extremities on activity of the sym-
pathetic nervous system. Therefore, this systematic review
and meta-analysis was undertaken to evaluate the effects of
joint mobilisation targeting any anatomical region, spine or
extremity, on changes in clinical manifestations (i.e. skin con-
ductance or skin temperature) of sympathetic nervous system
activity in individuals with and without pain.
A secondary objective was to examine the differences in
changes in sympathetic nervous system activity in relation
to the body region targeted by the mobilisation (spine vs
extremities).
Methods
This review followed the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA)
guideline [26], and was registered on PROSPERO
(CRD42018089991).
Literature database search
Electronic literature searches were conducted using MED-
LINE, EMBASE, AMED, CINAHL, EBSCO, PubMed,
PEDro, Cochrane Collaboration Trials Register and SCOPUS
from their inception to 31 March 2018. When these databases
allowed limits, searches were restricted to randomised clini-
cal trials, including pilot studies. The reference lists of papers
identified in the database searches were also screened.
Population
Adults (aged ≥18 years) with or without pathology were
included in this review. The search strategy had to include
at least one of the following key words: healthy subjects OR
healthy volunteers OR musculoskeletal pain.
Intervention
Joint mobilisation (low frequency/high amplitude) was
performed in isolation and manually (i.e. no instruments).
The search strategy had to include one of the following key
words: spinal mobilisation OR manual therapy OR mus-
culoskeletal mobilisation OR peripheral mobilisation OR
joint-biased manual therapy.
Comparator
Acceptable comparators included any type of placebo,
sham or no intervention. The search strategy had to include
one of the following key words: sham OR placebo OR control
OR no intervention.
120 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
Outcomes
Any outcome evaluating the function of the sympathetic
nervous system (i.e. skin conductance or skin temperature)
was evaluated. An increase in skin conductance or a decrease
in skin temperature is indicative of excitatory activation of
the sympathetic nervous system. The search strategy had to
include at least one of the following key words: skin conduc-
tance OR skin temperature OR galvanic skin response OR
sympathetic nervous system.
The search strategy for each database is shown in
Appendix 1.
Inclusion criteria for article selection
For inclusion in this systematic review and meta-analysis,
a study had to describe an experimental procedure (clinical
trial) with a PEDro scale score ≥5 points that applied a non-
thrust joint mobilisation. In this review, high-velocity/low-
amplitude thrust manipulation interventions were excluded.
No restriction was placed on the language of publication or
the body area studied.
Study selection
Articles identified through the database searches were
reviewed independently by two authors. First, any duplicates
were removed. Second, titles and abstracts were screened for
eligibility. Next, the full text of the remaining studies was
screened for eligibility criteria. The authors were required
to achieve consensus on each included trial. In case of dis-
agreement between the two authors, a third author decided
whether the article should be included. The rate of agreement
between the authors was 95%.
Data extraction
Data from each trial were extracted independently by two
authors. A standardised data extraction form containing data
on sample size, participants, diagnosis, interventions, study
design, results and outcomes was used. The authors were
required to achieve consensus on each item on the data extrac-
tion form. In case of disagreement between the authors, a third
author made the final decision.
Assessment of risk of bias
Included trials were critically appraised for potential risk
of bias (RoB) by two researchers using the Cochrane RoB
assessment tool [27]. If blinding of the patient or therapist
was impossible for technical reasons (as commonly happens
in manual therapy trials), it was rated as ‘not applicable’. The
domain ‘incomplete outcome data’ was considered to induce
RoB if data were statistically analysed per protocol and losses
to follow-up were ≥20% [28].
Level of evidence
The Grading of Recommendations Assessment, Devel-
opment and Evaluation (GRADE) approach was used to
evaluate the quality of evidence [29]. Evidence was classi-
fied as high, moderate, low or very low based on RoB of
the trials. The quality of evidence was calculated based on
the presence of study limitations (RoB), indirectness of evi-
dence, unexplained heterogeneity or inconsistency of results,
imprecision of results, and high probability of publication
bias [30]. Two authors assessed the quality of evidence and
RoB independently. In the case of controversy, a third author
was consulted for the final decision.
Statistical data analysis
Review Manager 5.3 was used for quantitative examina-
tion of the effects of joint mobilisation on skin conductance
and temperature. Due to the methodological variability of the
studies and the different variables used as outcomes, stan-
dardised mean differences (SMD) with their associated 95%
confidence intervals (CI) were calculated using the random
effects model. Differences between a joint mobilisation group
and a control or placebo group were compared. Those vari-
ables that expressed changes in skin conductance or skin
temperature during the intervention were selected. If these
data were not provided, data reporting the effect over the
total measurement period were used. To examine subgroup
differences, effects on outcomes were compared by anatom-
ical region of joint mobilisation (spine vs extremities). SMD
values of <0.5, 0.5–0.8 and >0.8 were considered small, mod-
erate and large, respectively.
Heterogeneity of the studies was evaluated using the I2
statistic. The Cochrane group has stated that I2 of 0%–40%,
30%–60%, 50%–90% and 75%–100% may represent unim-
portant heterogeneity, moderate heterogeneity, substantial
heterogeneity and considerable heterogeneity, respectively
[31]. Asymmetry of data was evaluated using funnel plots
with the Egger’s test (when possible) to indicate the possible
risk of publication bias of small trials with negative results
(see online supplementary material).
Results
Literature search
The literature search of electronic databases identified
465 studies for review after the removal of duplicates. Four
hundred and thirty-nine (n = 439) studies did not fit the
inclusion criteria, based on examination of titles/abstracts.
Another eight trials were excluded for the following reasons:
lack of a comparison group, not compared with control or
placebo/sham groups [16,32,33], technique applied was a
high-velocity/low-amplitude thrust manipulation [23,34,35],
and several techniques were applied in the same session
[36,37]. Finally, 18 articles were included in the system-
 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
Fig. 1. Study search concerning skin conductance and skin temperature with the application of joint mobilisations.
atic review [7,13–15,17–20,22,38–46] and 17 trials were
included in the meta-analysis [7,13–15,17–20,22,38–45]
as one was excluded [46] due to lack of available data
(Fig. 1). Another ongoing clinical study was identified
in clinicaltrials.gov but was not included in the review
(NCT02826590).
Included trials
A description of the studies included in the systematic
review is given in Table 1. Seven studies used a randomisa-
tion procedure for group allocation [17–20,22,32,45], and
the other 11 studies used cross-over designs where par-
ticipants received all interventions in a random sequence
[7,13,15,38–43,46]. Fourteen studies examined the effect of
joint mobilisation in healthy people [14,15,17–20,39–46],
and the other four studies included symptomatic popula-
tions: individuals with elbow pain [13,38], neck pain [7] or
cervical–craniofacial pain [22].
Various joint mobilisation interventions were
applied, including posterior–anterior joint mobilisation
[7,14,18,40,41,44,45], unilateral lateral glides [38,39,46],
mobilisation with movement [13,15,17,20], sustained
121
natural apophyseal glide (SNAG) mobilisation and
anterior–posterior mobilisation [22,42]. In addition, var-
ious areas were targeted, including the cervical spine
[7,14,22,38–41,43], thoracic spine [15,20,45,46], lumbar
spine [17–19,44], elbow [13] and shoulder [42].
Every study comparing joint mobilisation with a control
intervention (n = 14) found a significant increase in skin con-
ductance with joint mobilisation [7,13–15,17–19,38–44]. Of
the 14 studies comparing joint mobilisation with a placebo
group, 10 studies reported a significant increase in skin con-
ductance [7,13–15,18,22,38,39,42,44] and four studies did
not [19,20,43,45].
Five of the 10 studies [7,13–15,42] comparing joint mobil-
isation with a control group found a significant decrease in
skin temperature with joint mobilisation. In addition, two
studies found a significant decrease in skin temperature with
joint mobilisation compared with placebo [13,15].
Risk of bias
Table 2 summarises the RoB assessment of the trials.
None of the trials were able to blind the therapists, and seven
studies were rated as ‘unclear’ for allocation concealment

Table 1
Description of the studies included in the systematic review and meta-analysis (year of publication).
Authors
Petersen et al. 1993 [14]
Slater et al. 1994 [15]
Vicenzino et al. 1994 [39]
Chiu and Wright 1996 [40]
Vicenzino et al. 1998 [38]
Simon et al.1997 [42]
Subjects
16 healthy subjects received all conditions
22 healthy subjects received all conditions
34 healthy subjects received all conditions
16 healthy subjects received all conditions
24 subjects with unilateral epicondylalgia.
All subjects received all conditions.
19 healthy subjects received all conditions
Groups
I: PA Grade III central mobilisation on C5. Three series of
1 minute each.
P: Soft touch with the thumbs over the spinous process of C5.
The position was maintained without movement. Three series
of 1 minute each.
C: No contact with the researcher.
I: ‘Sympathetic slump’ over the right sympathetic trunk in
sitting position with left lateral flexion of the trunk. In this
position, PA unilateral mobilisation is performed (Grade IV)
over the T6 costovertebral joint.
P: Same position as experimental position but with soft touch at
the T6 level.
C: Supine position without manual contact.
I: Grade III left lateral glide of C5/C6 with the upper limb in the
tension test 1 position.
I2: Grade III left lateral glide of C5/C6 with the upper limb in
the tension test 2b position.
P: Manual contact but no position was performed in the
application of tests 1 and 2b.
C: Therapist next to the head of the subject without establishing
any manual contact.
I: Grade III central PA over C5 at 2 Hz.
I2: Grade III central PA over C5 at 0.5 Hz.
C: Control.
I: Grade III left lateral glide of C5/C6 with motion segment
directed contralaterally to the affected upper limb.
P: Manual contact but no oscillatory movement.
C: Subject was positioned for the above conditions without any
manual contact.
I: Grade III AP over the glenohumeral joint.
P: Arm and shoulder in a 90◦ position.
C: Same position during the measurements.
122
Results
I produced a significant reduction in skin
temperature and a significant increase in skin
conductance compared with P or C. No
differences between P and C were found.
M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
I produced a significant increase in skin
conductance and a significant reduction in
skin temperature during the treatment
compared with P or C. No differences
between P and I were found.
I and I2 produced a significant reduction in
skin temperature and a significant increase in
skin conductance compared with P and C.
No differences between I and I2 or between
P and C were found.
I produced a significant increase in skin
conductance compared with I2 and C. No
significant differences in skin temperature
were found between C and I and I2.
I produced a significant increase in skin
conductance and a significant reduction in
skin temperature compared with P and C.
I produced increase in skin conductance
compared with P and C. No differences in
reduction of skin temperature between I and
P were found. Significant differences in
reduction in skin temperature were found
between I and C.
Table 1 (Continued)
Authors
Chiu and Wright 1998 [41]
Sterling et al. 2001 [7]
Cleland et al. 2002 [20]
Paungmali et al. 2003 [13]
Moulson and Watson 2006 [43]
Perry and Green 2008 [44]
Jowsey and Perry 2010 [45]
Subjects
17 healthy subjects received all conditions
30 patients with cervical pain for >3 months
and C5/6 dysfunction. All subjects
participated in all conditions
12 healthy subjects, six per group
24 patients with lateral epicondylalgia
received all conditions
16 asymptomatic subjects received all
conditions
45 healthy subjects (males), 15 per group
36 healthy subjects, 18 per group
Groups
I1: Grade III unilateral PA over right posterior surface C5
articular.
I2: C5 transverse vertebral pressure Grade II mobilisation.
P: Grade III central PA over C5 at 0.5 Hz.
C: Control.
I: Grade III unilateral PA oscillatory technique over the
symptomatic side over the C5/C6. Three series of 1 minute.
P: Manual contact on the symptomatic side over the C5/C6
joint without any movement.
C: No physical contact between the subject and the researcher.
I: ‘Sympathetic slump’ (Grade IV) over the T6 costovertebral
joint.
P: Sitting position with the hand applying soft touch at the T6
level.
I: Lateral elbow glide.
P: Manual contact was applied, and the patient was performing
the grip without pain.
C: Without manual contact, and the patient was performing the
grip without pain.
I: Cervical SNAG performed at C5/6 at the same time as the
subject turned their head to the right (three times).
P: The researcher performed the same contact over the
vertebrae but did not apply the accessory glide of the SNAG.
The subject turned their head to the right and to the neutral
position while the therapist maintained contact over C5/C6 with
their thumbs (three times).
C: No contact with the patient. Neutral position of the head.
I: Grade III unilateral oscillatory mobilisation over the left
zygapophyseal joint of L4/L5 at 2 Hz.
P: Same hand position of the therapist on the area but applying
a very soft touch and without the application of oscillatory
movement.
C: Same patient position but without any manual contact or
movement.
I: Grade III PA rotational mobilisation over T4 at 0.5 Hz.
P: Same position as real technique.
Results
I2 produced a significant increase in skin
conductance compared with C, P and I1. I1
did not produce a significant increase in skin
conductance compared with P or C. No
differences were found in skin temperature
between all groups.
I produced a significant increase in skin
conductance compared with P and C, and a
significant reduction in skin temperature
compared with C but similar changes to P.
Minimum skin temperature was greater for I
M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
compared with P and C.
Non-significant changes in skin conductance
and skin temperature between P and I.
Lateral elbow glide produced a significant
increase in skin conductance and a
significant reduction in skin temperature
compared with P and C.
I did not produce a significant reduction in
skin temperature during the intervention and
post-intervention period compared with P
and C. I produced a significant increase in
skin conductance compared with P and C in
the intervention and post-intervention period.
I produced a significant increase in skin
conductance compared with P or C during
treatment.
I produced a significant increase in skin
conductance in the right extremity during the
post-treatment period compared with P. No
differences in skin conductance were
observed between I and P.
123

Table 1 (Continued)
Authors
Moutzouri et al. 2012 [19]
La Touche et al. 2013 [22]
Tsirakis and Perry 2015 [17]
Piekarz and Perry 2016 [18]
Zegarra-Parodi et al. 2016 [46]
I, intervention; C, control; P, placebo; PA, postero-anterior; AP, antero-posterior; PPT, pain pressure threshold; SNAG, sustained natural apophyseal glide.
Subjects
45 healthy participants, 15 per group
32 patients with craniofacial chronic pain, 16
per group
45 healthy men, 15 per group
60 healthy participants, 15 per group
32 healthy participants received all
conditions
Groups
I: SNAG mobilisation to the spinous process of L4.
P: The researcher placed their hands in the same location over
the column but did not apply glide with the lumbar movement.
C: Participant was sitting with the therapist behind them without
any manual contact and without performing any movement.
I: AP(QP) mobilisation (C0 to C3) at 0.5 Hz.
P: Hands on the occipital region. Same as before, but without
mobilisation.
I: Medial glide of the fourth lumbar vertebrae with leg
movement in extended position (hip flexion).
P: Performed in the same way as the real technique but the hand
on the spinous process does not perform the medial accessory
glide on the vertebral segment. Same pressure is applied.
C: The participant stayed in the left lateral decubitus position
and did move their leg or receive manual contact.
I1: PA mobilisation with 94 to 109 N force at 3 Hz. Three series
of 1 minute each.
I2: PA mobilisation with 94 to 109 N force at 2 Hz. Three series
of 1 minute each.
P: Same hand position but statically applied pressure over L4
during three periods of 1 minute each with a force of 101 N.
I1: Lateral glide on T1 at 40% of PPT for low-pressure
mobilisation.
I2: Lateral glide of T1 at 80% of PPT for high-pressure
mobilisation.
C: Control (without touching).
124
Results
I produced a significant increase in skin
conductance compared with C, but similar
changes as P. No differences in skin
conductance were found between P and C.
I produced a significant increase in skin
conductance compared with C, but similar
changes as P. No differences in skin
conductance were found between P and C.
M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
I produced an increase in skin conductance
over time and sessions compared with P. No
differences in skin temperature were
observed between I and P.
I produced a significant increase in skin
conductance in the right leg during the
intervention period compared with C. A
non-significant increase in the left leg was
found during the intervention and
post-intervention period compared with C
and P.
I1 produced a significant increase in skin
conductance compared with P and C during
the intervention period. I1 produced a
significant increase in skin conductance
compared with C during the
post-intervention period. I2 did not produce
a significant increase in skin conductance
compared with C, P or I1.
No significant changes in skin temperature
were observed among the three groups.
 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132 125

Table 2
Risk of bias of randomised clinical trials included in the systematic review and meta-analysis.
Study 1 2 3 4 5 6 7 8
Petersen et al. 1993 [14] + + + NA + + + –
Slater et al. 1994 [15] ? ? + NA + + + –
Vicenzino et al. 1994 [39] ? ? + NA + + + –
Chiu and Wright 1996 [40] ? ? + NA + + + –
Simon et al. 1997 [42] ? ? ? NA + + + –
Chiu and Wright 1998 [41] + + ? NA + + + –
Vicenzino et al. 1998 [38] + + ? NA + + + ?
Sterling et al. 2001 [7] + + + NA + + + –
Cleland et al. 2002 [20] ? – ? NA + + + +
Paungmali et al. 2003 [13] + + – NA + + + –
Moulson and Watson 2006 [43] ? ? + NA ? + + –
Perry and Green 2008 [44] + + + NA + + + +
Jowsey and Perry 2010 [45] ? ? + NA + + + +
Moutzouri et al. 2012 [19] + – + NA ? + + +
La Touche et al. 2013 [22] + – + NA + + + +
Tsirakis and Perry 2015 [17] + + + NA + + + +
Zegarra-Parodi et al. 2016 [46] + ? – NA – + + –
Piekarz and Perry 2016 [18] + + + NA + + + +
1, sequence generation; 2, allocation concealment; 3, participant blinding; 4, therapist blinding; 5, assessor blinding; 6, incomplete outcome data; 7, selective
reporting; 8, other risks of bias; +, low risk of bias; –, high risk of bias;?, unclear risk of bias; NA, not applicable.

[15,39,40,42,43,45,46] as these data was not reported. In gen-
eral, the RoB of the trials included in the meta-analysis was
low or unclear.
Changes in skin conductance
Comparisons between joint mobilisation groups (during
the intervention period) and control groups for changes in
skin conductance are shown in Fig. 2. The meta-analysis
found a significant increase in skin conductance with a large
effect size (SMD 1.21, 95% CI 0.88 to 1.53, n = 269) but high
heterogeneity (I2 = 65%) after joint mobilisation compared
with a control intervention. The subgroup analysis (spine
vs extremity) found no differences (P = 0.169) and moder-
ate heterogeneity of the subgroups (I2 = 42.7%). The funnel
plot of comparison of skin conductance between treatment
and control groups indicates possible publication bias (Suppl.
Fig. 1, see online supplementary material).
Comparisons between joint mobilisation groups (during
the intervention period) and placebo groups for skin con-
ductance are shown in Fig. 3. The meta-analysis found an
increase in skin conductance with a moderate effect size
(SMD 0.73, 95% CI 0.51 to 0.96, n = 293) and moderate het-
erogeneity (I2 = 39%) after joint mobilisation compared with
a placebo intervention. The subgroup analysis revealed no
significant differences (P = 0.15) and moderate heterogene-
ity of the subgroups (I2 = 42.8%). The funnel plot comparing
the effect of joint mobilisation with a placebo intervention for
skin conductance indicates no publication bias (Suppl. Fig.
2, see online supplementary material).
Changes in skin temperature
Fig. 4 summarises the comparison between the joint
mobilisation groups (during the intervention period) and the
control groups for skin temperature. The results showed a
decrease in skin temperature with a large effect size (SMD
−0.92, 95% CI −1.47 to −0.37, n = 128) but high hetero-
geneity (I2 = 76%) after joint mobilisation compared with the
control intervention. Subgroup analysis (spine vs extremity)
revealed no significant differences (P = 0.89) and was homo-
geneous (I2 = 0%). The funnel plot comparing the effect of
joint mobilisation with a control intervention for skin tem-
perature indicates no risk of publication bias (Suppl. Fig. 3,
see online supplementary material).
Fig. 5 summarises the comparison between the joint
mobilisation groups (during the intervention period) with the
placebo groups for skin temperature. When comparing the
joint mobilisation group with the placebo group, there was a
small to moderate effect size (SMD −0.50, 95% CI −0.82
to −0.18, n = 134) and low heterogeneity (I2 = 0%) reporting
a decrease in skin temperature after joint mobilisation. Sub-
group analysis (spine vs extremities) revealed no significant
differences (P = 0.38) and was homogeneous (I2 = 0%). The
funnel plot comparing the effects of joint mobilisation with a
placebo intervention for skin temperature indicates low risk
of publication bias (Suppl. Fig. 4, see online supplementary
material).
Quality of evidence (GRADE)
The details of GRADE assessment of the included tri-
als are displayed in Table 3. Most of the trials included
in this meta-analysis had low or unclear RoB. Although
significant differences were found, the evidence was
downgraded, particularly for level of heterogeneity (incon-
sistency).
126 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132

Fig. 2. Comparison between the effects of joint mobilisation and control condition on skin conductance during the intervention period.

Fig. 3. Comparison between the effects of joint mobilisation and placebo condition on skin conductance during the intervention period.
Table 3
GRADE evidence profile for mobilisation interventions in the sympathetic nervous system.
Quality assessment Summary of findings

Number of participants
Comparison Outcome Number of Risk of biasa Inconsistencyb Indirectnessc Imprecisiond Publication Subjects in Subjects in Estimate SMD Quality
trials (design) biase intervention control group (95% CI)
group
Mobilisation Skin Fourteen RCTs Low Serious. Serious Not serious Strongly 269 269 1.21 (0.88 to Very low
interventions vs conductance suspected 1.53)
control High heterogeneity
(I2 = 65%)

M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132

Mobilisation Skin Seven RCTs Low Not serious. Serious Not serious Undetected 153 153 1.12 (0.87 to Moderate
interventions vs conductance 1.37)
control (cervical Low heterogeneity
region) (I2 = 4%)
Mobilisation Skin One RCTs Low NA Not serious Serious NA 13 13 2.23 (1.22 to Moderate
interventions vs conductance 3.24)
control (thoracic
region)
Mobilisation Skin Four RCTs Low Serious. Not serious Serious Undetected 60 60 0.85 (0.4 to 1.3) Low
interventions vs conductance
control (lumbar Moderate heterogeneity
region) (I2 = 52%)
Mobilisation Skin Two RCTs High Very serious. Serious Serious NA 43 43 1.62 (−0.77 to Very low
interventions vs conductance 4.01)
control (upper limbs High heterogeneity
region) (I2 = 95%)
Mobilisation Skin Seven RCTs Low Serious. Serious Serious Undetected 128 128 −0.92 (−1.47 Very low
interventions vs temperature to −0.37)
control High heterogeneity
(I2 = 71%)
Mobilisation Skin Four RCTs Low Serious. Not serious Serious NA 72 72 −0.78 (−1.41 Low
interventions vs temperature to −0.16)
control (cervical High heterogeneity
region) (I2 = 69%)
Mobilisation Skin One RCT Low NA Not serious Serious NA 13 13 −0.92 (−1.74 Moderate
interventions vs temperature to −0.10)
control (thoracic
region)
Mobilisation Skin Two RCTs High Very serious. Serious Serious NA 43 43 −1.26 (−3.27 Very low
interventions vs temperature to 0.75)
control (upper limbs High heterogeneity
region) (I2 = 94%)

127
Table 3 (Continued)
Quality assessment Summary of findings

128
Number of participants
Comparison Outcome Number of Risk of biasa Inconsistencyb Indirectnessc Imprecisiond Publication Subjects in Subjects in Estimate SMD Quality
trials (design) biase intervention control group (95% CI)
group
Mobilisation Skin Sixteen RCTs Low Not serious. Serious Not serious No 293 293 0.73 (0.51 to Moderate
interventions vs conductance 0.96)
placebo Low heterogeneity
(I2 = 39%)
Mobilisation Skin Seven RCTs Low Not serious. Serious Not serious No 153 153 0.98 (0.68 to Moderate
interventions vs conductance 1.27)
placebo (cervical Low heterogeneity
region) (I2 = 33%)
Mobilisation Skin Three RCTs Low Not serious. Not serious Serious NA 37 37 0.54 (0.07 to Moderate

M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132

interventions vs conductance 1.01)
placebo (thoracic Homogeneous
region) (I2 = 0%)

Mobilisation Skin Four RCTs Low Serious. Not serious Serious NA 60 60 0.55 (0.05 to Low
interventions vs conductance 1.06)
placebo (lumbar Moderate heterogeneity
region) (I2 = 46%)
Mobilisation Skin Two RCTs High Not serious. Serious Serious NA 43 43 0.39 (−0.15 to Low
interventions vs conductance 0.93)
placebo (upper limbs Moderate heterogeneity
region) (I2 = 35%)
Mobilisation Skin Eight RCTs Low Not serious. Serious Serious Undetected 134 134 −0.50 (−0.82 Low
interventions vs temperature to −0.18)
placebo Low heterogeneity
(I2 = 39%)
Mobilisation Skin Four RCTs Low Serious. Serious Serious NA 72 72 −0.70 (−1.23 Very low
interventions vs temperature to −0.17)
placebo (cervical Moderate heterogeneity
region) (I2 = 59%)
Mobilisation Skin Two RCTs Low Not serious. Not serious Serious NA 19 19 −0.16 (−0.80 Moderate
interventions vs temperature to 0.48)
placebo (thoracic Homogeneous
region) (I2 = 0%)

Mobilisation Skin Two RCTs Low Not serious. Serious Serious NA 43 43 −0.31 (−0.74 Low
interventions vs temperature to 0.11)
placebo (upper limbs Homogeneous
region) (I2 = 0%)

RCT, randomised controlled trial; SMD, standardised mean difference; NA, not applicable.
a No risk of bias was found in any study.
b I2 > 40%: serious; I2 > 80%: very serious.
c No indirectness of evidence was found in any study.
d n < 300, serious; n < 300 and estimated effect little or absent, very serious.
e Based on funnel plot analysis.
 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132 129

Fig. 4. Comparison between the effects of joint mobilisation and control condition on skin temperature during the intervention period.

Fig. 5. Comparison between the effects of joint mobilisation and placebo condition on skin temperature during the intervention period.

Discussion joint mobilisation applied to the spine and joint mobilisation

The main objective of this systematic review and meta-
analysis was to evaluate changes in clinical manifestations
(i.e. skin conductance and/or skin temperature) of sympa-
thetic nervous system activity in subjects with and without
pain. This study also examined if changes were different if
mobilisation was applied to the spine or the extremities. This
meta-analysis found evidence suggesting that joint mobili-
sation is able to produce a sympathetic-excitatory effect as
all changes were excitatory in nature (i.e. an increase in skin
conductance and a decrease in skin temperature) compared
with control or placebo interventions, indicating sympa-
thetic upregulation in individuals with and without pain.
Additionally, no significant differences were found between
applied to the extremities.
Current findings support a sympathetic-excitatory effect
of joint mobilisation, and that this effect is not related to
the region of application. These results are similar to the
meta-analysis conducted by Chu et al. [24], which found an
increase in skin conductance (large effect) and a decrease in
skin temperature (moderate effect) after the application of
spinal manipulation or mobilisation. The fact that no dif-
ferences existed between area of application supports the
results of the systematic review by Kingston et al. [11],
which found similar sympathetic-excitatory activation inde-
pendent from the spine region where the mobilisation was
applied. Nevertheless, the present meta-analysis is the first
to investigate the effects of joint mobilisation applied to the
130 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132
peripheral joints (extremities) on sympathetic nervous system
activity.
An interesting finding of this meta-analysis was a reduc-
tion in effect size, from large to moderate, for skin
conductance or skin temperature when joint mobilisation
was compared with placebo rather than a control condition,
which would support a small effect of placebo on the sympa-
thetic nervous system. Future studies should investigate the
effect of placebo on activation of the sympathetic nervous
system.
Different theories can potentially explain the effect of
joint mobilisation on sympathetic nervous system activity.
First, several studies have observed changes in the sym-
pathetic nervous system concomitant with an hypoalgesic
effect supporting activation of the periaqueductal grey mat-
ter [7,10–12,43,47]. In fact, these responses are similar to
those found in mice receiving electrical stimulation of the
midbrain, associated with a typical dangerous response.
Therefore, this may be the result of a stress response from
activation of the dorsal periaqueductal grey matter. Findings
from this meta-analysis are consistent with the hypothesis
that a sympathetic-excitatory response may be related to a
stress response. In agreement with this, Plaza-Manzano et al.
[8] observed an increase in neurotensin, a neurotransmitter
involved in the stress response and serotoninergic descend-
ing pathways, after application of a thoracic manipulation.
Another hypothesis explaining the sympathetic-excitatory
effect may be stimulation of the ganglia at the respective
vertebral level [11]. Some studies observed greater effects
on the ipsilateral side of joint mobilisation, suggesting acti-
vation of sympathetic fibres through spinal mobilisation
[15,17,44,45]. However, others found bilateral responses
after spinal mobilisation [7,20,32,39,43]. It is possible that
the sympathetic-excitatory response after joint mobilisation
is not related to a single mechanism, and both mechanisms
may act simultaneously. In fact, as no difference was found in
the sympathetic-excitatory response between joint mobilisa-
tion targeting the spine or upper extremities, it is possible
that the mechanisms underlying the sympathetic nervous
system effect of joint mobilisation may involve central mech-
anisms, suggesting that it might not matter which joint is
mobilised.
It is also plausible that different sympathetic nervous sys-
tem activation mechanisms may be induced according to the
mobilisation technique: glide technique vs SNAG, unilateral
techniques or high-frequency mobilisation [17,45]. In fact,
some trials showed that when oscillatory techniques were not
performed, no differences in skin conductance were found
compared with the placebo group [17,19,20,43]. Therefore,
the oscillatory characteristic of joint mobilisation seems to be
of particular relevance for this effect. In fact, several authors
found that frequencies of 2 Hz in the cervical region and 3 Hz
in the lumbar region resulted in greater activation of the sym-
pathetic nervous system [18,40]. However, others did not find
significant differences when using an oscillatory mobilisation
technique at a frequency of 0.5 Hz [45]. These results support
the hypothesis that different mechanisms of action may occur
with varying frequencies of oscillation, but further studies
should be conducted.
The sympathetic-excitatory effect has also been related
to an increase in pressure pain threshold and a decrease in
pain intensity in individuals with pain, suggesting that this
effect was associated with benefits for pain and function;
however, no previous study has investigated whether changes
in sympathetic nervous system activity were associated with
treatment benefits [7,13,22,38]. Therefore, it is not yet known
if the observed changes in sympathetic nervous system activ-
ity are clinically relevant or can only be used to explain the
underlying mechanisms of manual therapies. Significant dif-
ferences in sympathetic nervous system activity were not
observed between asymptomatic and symptomatic popula-
tions, in agreement with previous reviews [11,24]. Therefore,
current findings suggest that joint mobilisation is able to mod-
ulate sympathetic nervous system activity independently of
the presence or the absence of symptoms.
Some potential limitations to this meta-analysis should
be recognised. First, many of the trials included were con-
ducted on asymptomatic subjects; nevertheless, differences
were not noted between trials including healthy individu-
als and trials including a patient population (although their
number was small). Therefore, extrapolation of these results
to pain conditions should be considered with caution. Fur-
ther, the heterogeneity of the included studies was moderate
to high, and a risk of publication bias exists. Usually, asym-
metry of funnel plots is related to publication bias, but other
reasons, such as high heterogeneity or a small number of tri-
als, could justify this finding. These factors probably resulted
in a downgraded level of evidence (see Table 3). Finally, fur-
ther studies are necessary to examine changes in sympathetic
nervous system activity associated with the use of manual
therapies by controlling the type (mobilisation or manipu-
lation), the rate of oscillations, and their association with
treatment benefits in pain conditions.
Conclusions
This meta-analysis found moderate to high evidence
suggesting that application of joint mobilisation tech-
niques to the spine or the upper extremities produces a
sympathetic-excitatory effect, expressed as an increase in
skin conductance and a decrease in skin temperature, com-
pared with a control or placebo intervention. However, this
finding should be interpreted with caution due to hetero-
geneity of the data and the extrapolation to pain population
samples.
Ethical approval: This systematic review and meta-analysis
does not need Ethical approval according to Spanish Law.
Funding: No funds were received for this study.
Conflict of interest: None declared.
 M.J. Navarro-Santana et al. / Physiotherapy 107 (2020) 118–132 131

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